Differential inhibition of human CYP3A4 and Candida albicans CYP51 with azole antifungal agents

The inhibition by azole antifungals of human cytochrome CYP3A4, the major f orm of drug metabolising enzyme within the liver, was compared with their i nhibitory activity against their target enzyme, Candida albicans sterol 14 alpha-demethylase (CYP51), following heterologous expression in Saccharomyc es cerevisiae. IC50 values for ketoconazole and itraconazole CYP3A4 inhibit ion were 0.25 and 0.2 mu M. These values compared with much lower doses req uired for the complete inhibition of C. albicans CYP51, where IC50 values o f 0.008 and 0.0076 mu M were observed for ketoconazole and itraconazole, re spectively. Additionally, stereoselective inhibition of CYP3A4 and CYP51 wa s observed with enantiomers of the azole antifungal compounds diclobutrazol and SCH39304. In both instances; the RR( +) configuration at their asymmet ric carbon centres was most active. Interestingly, the SS(-) enantiomeric f orm of SCH39304 was inactive and failed to bind CYP3A4. as demonstrable by Type II binding spectra. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.